Measuring technique

ABSTRACT

The present invention relates to apparatuses for use in performing a quantitative analysis of a turbid pharmaceutical sample, e.g. a tablet, a capsule or a similar sample forming a pharmaceutical dose. A pharmaceutical, turbid sample ( 24, 57, 67 ) is irradiated with an excitation beam ( 20, 53, 64 ) of radiation, e.g. near infrared radiation. The intensity of emitted radiation ( 30 ) from the sample ( 24, 57, 67 ) is detected as function of both the wavelength of the emitted radiation and the photon propagation time through said sample ( 24, 57, 67 ). Optionally, the intensity of the emitted radiation ( 30 ) from the sample ( 24, 57, 67 ) is also detected in a spatially resolved manner.

FIELD OF THE INVENTION

The present invention relates to apparatuses for analysing a turbidpharmaceutical sample, e.g. a tablet, a capsule—especially a multipleunit pellet system (MUPS)—or a similar sample forming a pharmaceuticaldose.

BACKGROUND OF THE INVENTION

Non-invasive, non-destructible analysis of whole tablets can be carriedout by means of near-infrared (NIR) or Raman spectrometry. Today, NIRspectroscopy is a recognised technique for performing a fast analysis ofcompounds. The common feature of both these techniques is that theyutilise light in the NIR wavelength region (700–2500 nm, specifically700–1500 nm) where pharmaceutical tablets are relatively transparent(low molar absorptivity). That is, light can in this region penetratecompressed powders several mm:s why information in the content can beobtained emanating from the bulk of the tablet and not only from thesurface. A practical advantage of using NIR radiation is that diodelasers can be used.

One example of such an analysis is described in U.S. Pat. No. 5,760,399,assigned to Foss NIRsystems Inc. This document discloses an instrumentfor performing a NIR spectrographic transmission measurement of apharmaceutical tablet. This instrument is, however, capable of providingonly limited information as to the content of a sample, typically thequantity of a particular component in a sample. This prior-artinstrument cannot provide detailed information of, for example, thethree-dimensional distribution of one or more components in a sample.The technical background on which this limitation is based will befurther discussed in connection with the description of the presentinvention.

The prior art also includes a significant amount of methods for opticalimaging of human tissues, in particular for detecting disturbances ofhomogeneity, such as the presence of a tumour in human tissue. Thesemethods are generally qualitative measurements, not quantitative, in thesense that they primarily focus on determining the presence and thelocation of an inhomogeneity. These prior-art methods are not suitablefor performing a quantitative analysis on pharmaceutical, turbidsamples, such as tablets and capsules, in order to determine e.g.content and structural parameters.

SUMMARY OF THE INVENTION

According to a first aspect of the invention there is providedapparatuses for use in quantitative analysis of a turbid, pharmaceuticalsample, in particular a pharmaceutical tablet or capsule of anequivalent pharmaceutical dose.

According to the invention, the apparatuses comprises:

-   -   means for generating an excitation beam of radiation; and    -   means for focusing said excitation beam onto said sample.

According to one embodiment the apparatus also comprises:

-   -   means for intensity modulating said excitation beam; and    -   means for detecting all wavelengths simultaneously.

According to another embodiment the apparatus also comprises:

-   -   means for splitting said excitation beam into two beams (70,        74); and    -   means (68, 71) for detecting transmitted light and        non-transmitted light respectively.

The invention is based on the following principles. A sample to beanalysed by a spectrometric transmission and/or reflection measurementpresents a number of so called optical properties. These opticalproperties are (i) the absorption coefficient, (ii) the scatteringcoefficient and (iii) the scattering anisotropy. Thus, when the photonsof the excitation beam propagate through the turbid sample—intransmission and/or reflective mode—they are influenced by these opticalproperties and, as a result, subjected to both absorption andscattering. Photons that by coincidence travel along an essentiallystraight path through the sample and thus do not experience anyappreciable scattering will exit the sample with a relatively short timedelay. Photons that are directly reflected on the irradiated surfacewill also present a relatively short time delay, in the case ofmeasurements on reflected light. On the other hand, highly scatteredphotons (transmitted and/or reflected) exit with a substantial timedelay or phase difference. This means that all these emittedphotons—presenting different propagation times—mediate complementaryinformation about the sample.

In a conventional steady state (no time-resolution) measurement, some ofthat complementary information is added together since the emitted lightis captured by a time-integrated detection. Accordingly, thecomplementary information is lost in a conventional technique. Forinstance, a decrease in the registered light intensity may be caused byan increase in the sample scattering coefficient. However, theinformation about the actual cause is hidden, since all the emittedlight has been time-integrated.

According to the invention and in contrast to such prior-art NIRspectroscopy with time-integrated intensity detection, the intensity ofthe emitted radiation from the sample is measured both as a function ofthe wavelength and as a function of the photon propagation time throughsaid sample. Thus, the inventive method can be said to be bothwavelength-resolved and time-resolved. It is important to note that themethod is time-resolved in the sense that it provides information aboutthe kinetics of the radiation interaction with the sample. Thus, in thiscontext, the term “time resolved” means “photon propagation timeresolved”. In other words, the time resolution used in the invention isin a time scale which corresponds to the photon propagation time in thesample (i.e. the photon transit time from the source to the detector)and which, as a consequence, makes it possible to avoid time-integratingthe information relating to different photon propagation times. As anillustrative example, the transit time for the photons may be in theorder of 0, 1–2 ns. Especially, the term “time resolved” is not relatedto a time period necessary for performing a spatial scanning, which isthe case in some prior-art NIR-techniques where “time resolution” isused.

As a result of not time-integrating the radiation (and thereby “hiding”a lot of information) as done in the prior art, but instead timeresolving the information from the excitation of the sample incombination with wavelength resolving the information, the inventionmakes it possible to establish quantitative analytical parameters of thesample, such as content, concentration, structure, homogeneity, etc.

Both the transmitted radiation and the reflected radiation from theirradiated sample comprise photons with different time delay.Accordingly, the time-resolved and wavelength resolved detection may beperformed on transmitted radiation only, reflected radiation only, aswell as a combination of transmitted and reflected radiation.

The excitation beam of radiation used in the present invention mayinclude infrared radiation, especially near infrared radiation (NIR) inthe range corresponding to wavelengths of from about 700 to about 1700nm, particularly form 700 to 1300 nm. However, the excitation beam ofradiation may also include visible light (400 to 700 nm) and UVradiation. In this connection, it should also be stated that the term“excitation” should be interpreted as “illumination”, i.e. no chemicalexcitation of the sample is necessary.

Preferably, the step of measuring the intensity as a function of photonpropagation time is performed in time-synchronism with the excitation ofthe sample. In a first preferred embodiment, this time synchronism isimplemented by using a pulsed excitation beam, presenting a pulse trainof short excitation pulses, wherein each excitation pulse triggers theintensity measurement. To this end, a pulsed laser system or laserdiodes can be used. This technique makes it possible to perform a photonpropagation time-resolved measurement of the emitted intensity(transmitted and/or reflected) for each given excitation pulse, duringthe time period up to the subsequent excitation pulse.

In order to avoid any undesired interference between the intensitymeasurements relating to two subsequent pulses, such excitation pulsesshould have a pulse length short enough in relation to the photonpropagation time in the sample and, preferably, much shorter than thephoton propagation time.

To summarise, in this embodiment of the invention the intensitydetection of the emitted radiation associated with a given excitationpulse is time-synchronised with this pulse, and the detection of theemitted light from one pulse is completed before next pulse.

The data evaluation can be done in different ways. By defining theboundary conditions and the optical geometry of the set-up, iterativemethods such as Monte Carlo simulations can be utilised to calculate theoptical properties of the sample and indirectly content and structuralparameters. Alternatively, a multivariate calibration can be used for adirect extraction of such parameters. In multivariate calibration,measured data is utilised to establish an empirical mathematicalrelationship to the analytical parameter of interest, such as thecontent or structure of a pharmaceutical substance. When newmeasurements are performed, the model can be used to predict theanalytical parameters of the unknown sample.

In an alternative embodiment the radiation source is intensity modulatedin time. Then, frequency domain spectroscopy can be used for determiningphase shift and/or modulation depth of the emitted radiation from thesample. Thus, the phase and/or modulation depth of the emitted sampleradiation is compared with those of the excitation radiation. Thatinformation can be used to extract information about the time delay ofthe radiation in the sample. Moreover, the emitted radiation can bemeasured for a multitude of wavelengths to obtain spectral information.It should be noted that the above mentioned frequency domainspectroscopy is also a “time-resolved” technique according to theinvention, since it also provides information about the kinetics of thephoton interaction with the sample. With similar mathematical proceduresas above, the same quantitative analytical information can be extracted.

A pulsed excitation beam according to the first embodiment, and anintensity modulated excitation beam according to the second embodiment,share the common feature that they make it possible to identify—in saidexcitation beam—a specific “excitation time point” which can be used totrigger the detection of the emitted radiation from the sample, i.e. totime-synchronise the time-resolved detection with the excitation of thesample. This can be performed by letting the pulsed or modulated beamtrigger a photodetector or the equivalent, which in its turn triggersthe detection unit via suitable time-control circuitry.

The time detection may be implemented by the use of a time-resolveddetector, such as a streak camera. It may also be implemented by the useof a time-gated system, by which the detection of emitted radiation isperformed during a limited number of very short time slices instead ofthe full time course. The time length of each such time slice is only afraction of the detection time period during which the time resolveddetection is performed for each excitation. By measuring several such“time slices” a coarse time resolution is achieved. An attractivealternative is to measure wavelength resolved spectra at two such timegates, prompt light and delayed light. Furthermore, time-resolved datamay be recorded by means of other time-resolved equipment, transientdigitizers or equivalent.

In a further embodiment a Fourier transform detector is used, whereby amirror is scanned back and forth producing an interferogram. Theinterferogram will contain information about the light transmittedthrough the sample at all wavelengths. Since an interferogram is used,all wavelengths are monitored simultaneously. The result will be aspectrum of the transmitted light. The light source is intensitymodulated with a modulation driver at high frequency (MHz-GHz). Thephase and the modulation depth of the detected signal and the modulationdriver are compared and used as output signals. These will provideinformation about the time behaviour of the photon propagation throughthe sample. If the scanning speed of the moving mirror of the Fourierspectrometer is much slower than the light modulation frequency, a valuefor the phase difference and the modulation depth is obtained for eachposition of the moving mirror. Thus, the phase difference and themodulation depth are measured by a scan in the Fourier space and not ascan in the wavelength domain. Information about physically relevantparameters, such as contents or particle size, of the sample can beextracted by deconvolution techniques and chemometric models. Amultitude of modulation frequencies can be utilised for more accurateanalysis.

In yet a further embodiment intensity modulated light is directed onto asample. The transmitted or diffusely reflected light is detected by afast detector and a second detector detects the light before irradiatingthe sample. The signals from the two detectors are compared regardingthe phase difference and modulation depth. These two values areregistered for each wavelength in sequence and from these valuesinformation about, for example, contents can be extracted withdeconvolution techniques and chemometric models.

The wavelength resolved detection may be implemented in many different,conventional ways. It may be implemented by the use of a multi-channeldetector, such as microchannel plate or a streak camera. Use can be madeof light dispersive systems, such as (i) a spectrometer, (ii) awavelength dependent beam splitter, (iii) a non-wavelength dependentbeam splitter in combination with a plurality of filters for filteringeach of respective components for providing radiation of differentwavelength or wavelength band, (iv) a prism array or a lens systemseparating the emitted radiation from the sample into a plurality ofcomponents in combination with a plurality of filters, etc.

DESCRIPTION OF THE DRAWINGS

The above and other features and advantages of the invention are definedin the claims and described in greater detail below with reference tothe accompanying drawings, which illustrate preferred embodiments.

FIG. 1 a illustrates a set-up for performing a time-resolved andwavelength resolved analysis.

FIG. 1 b illustrates an embodiment where the excitation and thecollection of emitted light are performed at the irradiation side onlyof the sample.

FIG. 2 illustrates functional components for implementing the presentinvention.

FIG. 3 a is a streak camera image, illustrating an experimental resultof a wavelength-resolved and time-resolved tablet transmissionmeasurement according to the invention.

FIG. 3 b is a 3D plot of the streak camera image in FIG. 3 a.

FIG. 4 a is a streak camera image, illustrating an experimental resultof a time-resolved tablet transmission measurement according to theinvention, in combination with spatial resolution.

FIG. 4 b is a 3D plot of the streak camera image in FIG. 4 a.

FIG. 5 is diagram illustrating experimental results from transmissionmeasurements on two different tablet samples.

FIG. 6 illustrates an alternative set-up for performing a time-resolvedand wavelength resolved analysis.

FIG. 7 illustrates yet another alternative set-up for performing atime-resolved and wavelength resolved analysis.

FIG. 8 is a diagram illustrating experimental results from measurementsmade with the set-up in FIG. 7.

DESCRIPTION OF PREFERRED EMBODIMENTS

Referring now to FIG. 1 a, an apparatus according to a first embodimentfor performing a time-resolved analysis according to the inventioncomprises a Ti:sapphire laser 10 pumped by an argon laser 12. The laserbeam 14 thereby generated is amplified by a neodymium YAG amplifierstage 16 into an amplified laser beam 18. In order to create anexcitation beam 20 of “white” light, the laser beam 18 is passed througha water filled cuvette 22 via a mirror M1 and a first lens system L1.

A sample to be analysed is schematically illustrated at referencenumeral 24 and comprises a front surface 26 and a back surface 28. Thesample 24 is temporarily fixed in a sample-positioning unit (not shown).The excitation laser beam 20 is focused onto the front surface 26 ofsample 24 via a lens system L2/L3 and mirrors M2-M4. On the oppositeside of sample 24, the transmitted laser beam 30 is collected from thebackside by lens system L4/L5 and focused into spectrometer 32. In theillustrated set-up, the sample 24 may be a pharmaceutical, solid tablethaving a diameter of e.g. 9 mm. The excitation beam 20 may be focused ina spot of about 1 mm. In other embodiments, the excitation beam may befocused on the whole sample, or scanned over the sample.

In an alternative embodiment the apparatus is attached to for example afluidised bed for remote sampling of a selected part of the contents inthe bed.

As schematically illustrated in FIG. 1 a, the excitation beam 20 in thisembodiment is time-pulsed into a pulse train of short, repetitiveexcitation pulses P. The pulse length of each excitation pulse P isshort enough and the time spacing between two consecutive excitationpulses P is long enough in relation to the transit time of the beam(i.e. in relation to the time taken for each pulse to be completelymeasured in time), such that any interference is avoided between thedetected-light from one given excitation pulse P_(n) and the detectedlight from the next excitation pulse P_(n+1). Thereby, it is possible toperform a time-resolved measurement on the radiation from one excitationpulse P at a time.

From the spectrometer 32, the detected light beam 33 is passed via lenssystem L6/L7 to a time-resolved detection unit, which in this embodimentis implemented as a streak camera 34. The streak camera 34 used in anexperimental set-up according to FIG. 1 a was a Hamamutsu Streak CameraModel C5680. Specifically, the streak camera 34 has an entrance slit(not shown) onto which the detected light beam 33 from the spectrometer32 is focused. It should be noted that only a fraction of the lightemitted from the sample is actually collected in the spectrometer 32and, thereby, in the detection unit 34. As a result of passing throughthe spectrometer 32, the emitted radiation 30 from the sample 24 isspectrally divided in space, such that radiation received by the streakcamera 34 presents a wavelength distribution along the entrance slit.

The incident photons at the slit are converted by the streak camera intophotoelectrons and accelerated in a path between pairs of deflectionplates (not shown). Thereby, the photoelectrons are swept along an axisonto a microchannel plate inside the camera, such that the time axis ofthe incident photons is converted into a spatial axis on saidmicrochannel plate. Thereby, the time in which the photons reached thestreak camera and the intensity can be determined by the position andthe luminance of the streak image. The wavelength-resolution is obtainedalong the other axis. The photoelectron image is read out by a CCDdevice 36, which is optically coupled to the streak camera 34. The datacollected by the CCD device 36 is coupled to an analysing unit 38,schematically illustrated as a computer and a monitor.

In the set-up in FIG. 1 a, the intensity of the emitted light ismeasured as a function of time in time-synchronism with each excitationof the sample. This means that the detection unit comprising the streakcamera 34 and the associated CCD device 36 is time-synchronised with therepetitive excitation pulses P. This time-synchronism is accomplished asfollows: each excitation pulse P of the laser beam 14 triggers aphotodetector 42 or the equivalent via an optical element 40. An outputsignal 43 from the photodetector 42 is passed via a delay generator 44to a trig unit 46, providing trig pulses is to the streak camera 34. Inthis manner, the photon detection operation of the streak camera isactivated and de-activated at exact predetermined points in time afterthe generation of each excitation pulse P.

As mentioned above, the evaluation and analysis of the collected,time-resolved information can be done in different ways. Asschematically illustrated in FIG. 1 a, the collected data informationfrom each excitation is transferred from the streak camera 34 and theCCD device 36 to a computer 38 for evaluation of the information. MonteCarlo simulations, multivariate calibrations, etc as mentioned in theintroductory part of this application can be utilised in order tocalculate the optical properties of the sample and, indirectly, contentand structural parameters of the sample 24.

In the embodiment shown in FIG. 1 b, it is the transmitted radiation—thebeam 30—which is detected in a time-resolved manner. However, theinvention can also be implemented by detecting the radiation reflectedfrom the sample. FIG. 1 b schematically illustrates how an excitationbeam 20′ corresponding to excitation beam 20 in FIG. 1 a is focused viaa lens L3′ onto the front surface 26 of a sample 24. The photons of eachexcitation pulse will be reflected both as directly reflected photonsfrom the front surface 26 as well as diffusely backscattered photonswith more or less time delay. This directly reflected radiation as wellas the diffusely backscattered radiation is collected by a lens L4′ intoa detection beam 30′, corresponding to detection beam 30 in FIG. 1 a.

As stated above, it is possible to combine the embodiments illustratedin FIGS. 1 a and 1 b into one single embodiment, where both transmittedand backscattered light is detected and analysed in a time-resolved andwavelength-resolved manner according to the invention.

FIG. 2 schematically discloses the main functional components in anembodiment for implementing the inventive method, including a radiationgeneration unit 100 (components 10, 12 and 16 in FIG. 1 a), a samplepositioning unit 102, one or more wavelength dispersive/selectiveelements 104 (component 32 in FIG. 1 a), one or more detector units 106(components 34 and 36 in FIG. 1 a) and an analysing unit 108 (component38 in FIG. 1 a).

The water filled cuvette 22 producing white laser light in combinationwith the spectrometer 32 acting as a wavelength-dispersive element makesit possible to collect data that is both wavelength-resolved andtime-resolved. FIGS. 3 a and 3 b illustrate the experimental result ofsuch a detection. It should be noted that the time scale in both FIG. 3a and FIG. 3 b illustrate the intensity variation over time for onepulse only, although the actual data used for producing these figures isbased in accumulated data from many readings. The time axis in FIGS. 3 aand 3 b is in nano second scale.

FIG. 3 a illustrates a streak camera image pasted into a time-wavelengthdiagram, the light portions correspond to high intensity values. Theleft part of the image corresponds to detected photons having arelatively short time delay, whereas the right part of the imagecorresponds to photons with a relatively long delay time.

The 3D plot in FIG. 3 b corresponds to the image in FIG. 3 a. This 3Dplot clearly illustrates how the time-resolved spectroscopy according tothe invention results in an intensity measurement as a function of bothwavelength and photon propagation time. This 3D plot also clearlyillustrate that the total information content as obtained by the presentinvention is significantly greater than the information obtainable witha conventional time-integrated detection.

In FIG. 3 b, for each wavelength (such as for the wavelengths λ1 and λ2as identified in FIG. 3 b) there is a multitude of timely spacedintensity readings. Thus, for each wavelength it is possible to obtain afull curve of emitted (transmitted and/or reflected) intensity vs.propagation time. The form of these “time profiles” shown in FIG. 3 b isdependent on the relation between the optical properties of the analysedsample. With such a time-resolved and wavelength-resolved spectroscopy,it is possible to obtain information for describing the lightinteraction with the sample. As an example, this provides the basis-fordetermining an analytical concentration in a sample that is proportionalto the absorption coefficient but not related to the scattering. Asanother example, one might want to measure an analytical quantity thatcorrelates to the scattering properties of the sample instead.

As illustrated by the dashed lines t1 and t2 in FIG. 3 b, it is alsopossible to evaluate the emitted light by detecting the intensity duringfixed time slices. This would give a more coarse time resolution. In oneembodiment, wavelength-resolved spectra are measured at two time gatesonly—one for “prompt” light and one for “delayed” light.

The intensity-time diagram in FIG. 5 illustrates two experimental,time-resolved results from measurements on two different tablets. Byselecting suitable time gates where the difference is substantial, onecan easily distinguish different tablets from each other.

As an alternative to the set-ups illustrated in FIGS. 1 a and 1 b,instead of using the water cuvette 20 in combination with thespectrometer 32, it is possible to use wavelength selective lightsources, such as diode lasers. On the detector side, wavelengthselective detectors, such combinations of filters and detector diodes,can be used for each wavelength.

It is possible to combine the invention with spatial-resolved intensitydetection on the emitted light from the sample. In this context, theterm “spatial resolved” refers to a spatial resolution obtained for eachexcitation pulse. Especially, “spatial resolved” does not refer to aspatial resolution based on a scanning in time of the excitation beam inrelation to the sample. As an illustrative example, by removing thewater cuvette 22 and the spectrometer 32 in the FIG. 1 a set-up, thelight focused on the entrance slit of the streak camera would be spatialresolved along the slit, corresponding to a “slit” across the sample. Astreak camera image obtained by such a set-up is illustrated in FIG. 4a, and a corresponding 3D plot is illustrated in FIG. 4 b. In accordancewith FIGS. 3 a and 3 b discussed above, FIGS. 4 a and 4 b represent onepulse only; i.e. the spatial resolution illustrated does not correspondto any scanning of the excitation beam over the sample.

A further alternative set-up is illustrated in FIG. 6. A modulationdriver 50 intensity modulates 51 a light source 52. The light source isintensity modulated with a high frequency (MHz-GHz). The light source52, preferably a light emitting diode (LED), emits an excitation beam 53in broad range of wavelengths. The excitation beam 53 reaches a beamsplitter 54 where the excitation beam 53 is divided. One part of theexcitation beam 53 continues towards a mirror 56 where it is reflectedback to the beam splitter 54. The other part of the excitation beam 53continues towards a moving mirror 55 where it is reflected back to thebeam splitter 54. The two parts of the split excitation beam 53 arebrought together again at the beam splitter 54 where they continuetowards the sample 57. The sample 57 is thus irradiated and thetransmitted light detected by a detector 58. By scanning the movingmirror 55 back and forth, an interferogram is produced. Thisinterferogram contains information about the light transmitted throughthe sample at all wavelengths. By using an interferogram all wavelengthsare monitored simultaneously and the result will be a spectrum of thetransmitted light intensity. The signal 60 from the modulation driver 50is compared to the signal 59 from the detector 58 by a phase comparator61. From the comparison in the comparator 61 information can beextracted with deconvolution techniques and chemometric models.

A further alternative set-up of the present invention is illustrated inFIG. 7. In this embodiment the light source producing intensitymodulated light is made up of an array of diode lasers 62. The array ofdiode lasers 62 covers a wide range of wavelengths and a multiplexer 63is used to scan the various diode lasers 62 in the array, i.e. themultiplexer 63 executes the scan through the different wavelengths. Theproduced excitation beam travels through a set of mirrors, illustratedin FIG. 7 with one mirror 65, until it reaches a beam splitter 66 wherethe excitation beam 64 is divided up into two beams 70 and 74. One beam74 irradiates the sample 67 and the transmitted light is detected by aphotomultiplier 68. The other beam 70 is directed directly to aphotomultiplier 71 without irradiating the sample 67. The two signals 69and 72 produced by the photomultipliers 68 and 71 due to is the incidentbeams are compared in a phase comparator 73. These two signals 69 and 72are recorded for each wavelength in sequence according to the scanningof the diode laser array 62 by the multiplexer 63. The diagram in FIG. 8shows an example of the two signals 69 and 72 where the excitation sinuscurve corresponds to the beam 70 detected by photomultiplier 71 in FIG.7, i.e. the beam unaffected by the sample 67. The beam 74, afterirradiating the sample, is the detection sinus curve in FIG. 8.Information about physical parameters of the sample can be extractedfrom the type of diagram illustrated in FIG. 8 by comparing the twosinus shapes.

In either of the above embodiments the measurements can be carried outby remote sampling, i.e. the sample does not have to be positioned inspecific means. Therefore, the apparatuses can be placed to measure thecontents in a turbid, pharmaceutical sample flow and not only in aspecifically selected sample, e.g. a tablet or a capsule.

The foregoing is a disclosure of preferred embodiments for practicingthe present invention. However, it is apparent that device incorporatingmodifications and variations will be obvious to one skilled in the art.Inasmuch as the foregoing disclosure is intended to enable one skilledin the art to practice the instant invention, it should not be construedto be limited thereby, but should be construed to include suchmodifications and variations as fall within its true spirit and scope.

1. An apparatus for use in quantitative analysis of a turbidpharmaceutical sample, comprising: means for generating an excitationbeam of radiation comprising an intensity modulated light emitting diode(LED); means for intensity modulating said excitation beam; means forfocusing said excitation beam onto said sample; and means for detectingall wavelengths simultaneously.
 2. An apparatus as claimed in claim 1,wherein said means for detecting comprises a time-resolved detectionunit.
 3. An apparatus as claimed in claim 1, wherein said means fordetecting comprises a phase-resolved detection unit.
 4. An apparatus asclaimed in claim 1, wherein said means for detecting comprises atime-grated system.
 5. An apparatus as claimed claim 1, furthercomprising means for performing a spatial-resolved detection of saidintensity.
 6. An apparatus as claimed in claim 1, wherein saidpharmaceutical, turbid sample is a solid sample, in particular a tablet,a capsule, a bulk powder or an equivalent pharmaceutical dose.
 7. Anapparatus as claimed in claim 1, wherein said pharmaceutical, turbidsample is a dispersion.
 8. An apparatus as claimed in claim 1, whereinthe excitation beam comprises infrared radiation.
 9. An apparatus asclaimed in claim 8, wherein the infrared radiation is in the nearinfrared radiation (NIR).
 10. An apparatus as claimed in claim 1,wherein the radiation has a frequency in the range corresponding towavelengths from about 700 to about 1700 nm, particularly 700 to 1300nm.
 11. An apparatus as claimed in claim 1, wherein the excitation beamcomprises visible light.
 12. An apparatus as claimed in claim 1, whereinthe excitation beam comprises UV radiation.
 13. An apparatus as claimedin claim 1, wherein said means for generating an excitation beam ofradiation comprises one or more diode lasers.
 14. An apparatus asclaimed in claim 1, wherein said means for generating an excitation beamof radiation comprises an intensity modulated lamp.
 15. An apparatus asclaimed in claim 1, wherein said means for intensity modulating saidexcitation beam is a modulation driver.
 16. An apparatus as claimed inclaim 1, wherein said means for focusing the excitation beam on a sampleare parts of a Fourier spectrometer.
 17. An apparatus as claimed inclaim 15, wherein a phase comparator is arranged to compare signals fromthe modulation driver and from the means for detecting.
 18. An apparatusas claimed in claim 1, comprising means for positioning a turbidpharmaceutical sample.
 19. An apparatus for use in quantitative analysisof a turbid pharmaceutical sample, comprising: means for generating anexcitation beam of radiation comprising an intensity modulated lightemitting diode (LED); means for focusing said excitation beam onto saidsample; means for splitting said excitation beam into two beams; andmeans for detecting transmitted light and non-transmitted lightrespectively.
 20. An apparatus as claimed in claim 19, wherein saidmeans for detecting comprises a time-resolved detection unit.
 21. Anapparatus as claimed in claim 19, wherein said means for detectingcomprises a phase-resolved detection unit.
 22. An apparatus as claimedin claim 19, wherein said means for detecting comprises a time-gratedsystem.
 23. An apparatus as claimed in claim 19, further comprisingmeans for performing a spatial-resolved detection of said intensity. 24.An apparatus as claimed in claim 19, wherein said pharmaceutical, turbidsample is a solid sample, in particular a tablet, a capsule, a bulkpowder or an equivalent pharmaceutical dose.
 25. An apparatus as claimedin claim 19, wherein said pharmaceutical, turbid sample is a dispersion.26. An apparatus as claimed in claim 19, wherein the excitation beamcomprises infrared radiation.
 27. An apparatus as claimed in claim 26,wherein the infrared radiation is in the near infrared radiation (NIR).28. An apparatus as claimed in claim 19, wherein the radiation has afrequency in the range corresponding to wavelengths from about 700 toabout 1700 nm, particularly 700 to 1300 nm.
 29. An apparatus as claimedin claim 19, wherein the excitation beam comprises visible light.
 30. Anapparatus as claimed in claim 19, wherein the excitation beam comprisesUV radiation.
 31. An apparatus as claimed in any claim 19, wherein saidmeans for generating an excitation beam of radiation comprises one ormore diode lasers.
 32. An apparatus as claimed in claim 19, wherein saidmeans for generating an excitation beam of radiation comprises anintensity modulated lamp.
 33. An apparatus as claimed in claim 19,wherein said means for generating an excitation beam of radiation is anarray of diode lasers and a multiplexer.
 34. An apparatus as claimed inclaim 19, wherein said means for detecting transmitted light andnon-transmitted light are photomultipliers.
 35. An apparatus as claimedin claim 19, wherein a phase comparator is arranged to compare thesignals from said means for detecting transmitted light andnon-transmitted light.
 36. An apparatus for use in quantitative analysisof a turbid pharmaceutical sample, comprising: means for generating anexcitation beam of radiation; means for intensity modulating saidexcitation beam comprising a modulation driver; means for focusing saidexcitation beam onto said sample; and means for detecting allwavelengths simultaneously.
 37. An apparatus for use in quantitativeanalysis of a turbid pharmaceutical sample, comprising: means forgenerating an excitation beam of radiation; means for intensitymodulating said excitation beam; means for focusing said excitation beamonto said sample; means for detecting all wavelengths simultaneously;and a phase comparator arranged to compare signals from the means forintensity modulating the excitation beam and from the means fordetecting all wavelengths simultaneously.
 38. The apparatus of claim 37wherein the means for intensity modulating comprises a modulationdriver.
 39. An apparatus for use in quantitative analysis of a turbidpharmaceutical sample, comprising: means for generating an excitationbeam of radiation comprising an array of diode lasers and a multiplexer;means for focusing said excitation beam onto said sample; means forsplitting said excitation beam into two beams; and means for detectingtransmitted light and non-transmitted light respectively.